Identification of potential mechanisms of quercetin in diabetic peripheral neuropathy through integrated network pharmacology and experimental validation.

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes characterized by oxidative stress and neuroinflammation. Quercetin, a natural flavonoid with antioxidant properties, has shown potential in treating various nerve injuries, but its mechanisms in DPN remain unclear. This research aims to explore the potential therapeutic mechanisms of quercetin in DPN through network pharmacology and experimental validation. In this study, streptozotocin (STZ)-induced diabetic rats were treated with quercetin for 12 weeks. Behavioral tests and histopathological examination were performed to evaluate nociceptive behaviors and sciatic nerve pathology, and biochemical and molecular assays were used to assess oxidative stress, inflammation, and myelin-related markers. Bioinformatics and network pharmacology were used to predict relevant targets and pathways, followed by in vivo validation in sciatic nerve tissues and in vitro verification using high glucose-exposed RSC96 Schwann cells. Quercetin improved pain thresholds and sciatic nerve morphology without significantly altering blood glucose or body weight. Moreover, quercetin restored the remyelination-related gene expression and attenuated oxidative stress and inflammatory responses in DPN rats. Bioinformatics and network pharmacology analyses indicated that the TXNIP/NLRP3 signaling played a key role. Subsequent in vivo and in vitro experiments further supported that quercetin reduced TXNIP expression and downregulated NLRP3 inflammasome-related gene expression. Our results indicate that quercetin attenuates DPN-like manifestations and mitigates oxidative stress and neuroinflammation. Its potential mechanism may be related to the regulation of TXNIP/NLRP3 inflammasome-related signaling, which lays a foundation for further research on DPN treatment.